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Regulation of Pharmacovigilance

Amarilys Vega, MD, MPH

The Center for Drug Evaluation and Research

Office of Surveillance and Epidemiology

August 22, 2011

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utline

Background a ety urve ance n t e ecyc e o

CDER-regulated Products

Postmarketing Safety Surveillance

Possible Regulatory Actions Based onPostmarketing Safety Data

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Pharmacovigilance1

The science and activities relatin to the

detection, assessment, understanding,

and prevention of adverse effects or any

other drug-related problems.

1

3

,

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Center for Drug Evaluation

an esearc

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Center for DrugEvaluation and

Approved 5/9/2011, http://www.fda.gov/downloads/AboutFDA/CentersOffices/OrganizationCharts/UCM254312.pdf, accessed 8/1/2011

Janet Woodcock, MD

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CDERs Core Functions

Oversight of

Postmarketing Safety

Product Quality Product Advertisin Promotion

linked to one of these activities

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Safety in the Lifecycle of FDA-regulated Products

A Post-Pre-

P

R

V

L

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Safety in the Lifecycle of FDA-regulated Products

Phase 1 Phase 2 Phase 3 APPost-

Pre-clinical

Safety Safety Safety

PR SafetySafety

Dosage

Efficacy Efficacy VA

BiologicalActivity

a e y oncerns

8Strategies and Actions to Minimize Risk

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Strategies and Actions to Minimize Risk

All Products have: ro uc a e ng

Routine pharmacovigilance

Postmarketing requirements

n ca r a s

Observational studies

9 Risk Evaluation and Mitigation Strategy (REMS)

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CDER Forum for International

October 17-21, 2011, College Park, MD

Point of ContactJustina A. Molzon MS Pharm JDCDERForum@fda.hhs.gov

For meeting informationhttp://www.fda.gov/Drugs/NewsEvents/ucm167011.htm

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E idemiolo OSE

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Surveillance &

Epidemiology

Gerald Dal Pan, MD, MHS

12Approved 4/29/2011, http://www.fda.gov/downloads/AboutFDA/CentersOffices/OrganizationCharts/UCM254438.pdf, accessed 8/1/2011

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OSE Mission

The Office of Surveillance andEpidemiology evaluates drug risks and

American People

To carr out its mission OSE workstogether with other offices in CDER

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OSEs Core Areas

Pharamcoepidemiology

Risk Management Medication Error Prevention

is tied to these areas

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Many Disciplines Carry Out

Safety Evaluators Drug Use Analysts

Epidemiologists

Social Science Analysts Risk Mana ement Anal sts

Safety Project Managers

Contracts specialists

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OSEs Roles

Most of OSEs work = Postmarketing Safety

OSE always reviews new product proprietary

names from a medication error perspective

OSE is sometimes involved with evaluation of

remarketin safet of new roducts

Examples: risk management, epidemiology studies,

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specific safety issues

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E idemiolo

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Medication Error Prevention

Division of Medication Error Prevention Analysisas regu a ory au or y or propr e ary name

review

errors

Incor orates in ut from Office of New Dru s OND Division of

Drug Marketing, Advertising, and Communications (DDMAC),

others

Identifies error-prone aspects of labels, labeling, &

packaging of drug products & provides

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recommendations to minimize user error

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E idemiolo

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OSE Role Postmarketing

Reviews and Evaluates SpontaneousReports

Pharmacoepidemiology

Drug utilization data

Regulatory research

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Postmarketing SafetyLaws, Regulations and

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Laws

The Federal Food, Drug, and Cosmetic Act

(including amendments) includes the basis for most regulatory activities for

human drug products, including postmarketing

drug safety Recently amended by the Food and Drug

m n s ra on men men s c o

Complete list of the lawshttp://www.fda.gov/RegulatoryInformation

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.

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Food and Drug Administration

Public Law 110-85 in September 27, 2007

Title I: Prescription Drug User Fee Amendments of 2007

Title II: Medical Device User Fee Amendments of 2007

Title III: Pediatric Medical Device Safety and Improvement Act of 2007

Title IV: Pediatric Research Equity Act of 2007

Title V: Best Pharmaceuticals for Children Act of 2007

Title VI: Reagan-Udall Foundation

Title VII: Conflicts of Interest

e : n ca r a a a ases

Title IX: Enhanced Authorities Regarding Postmarket Safety of Drugs

Title X: Food Safety

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Title XI: Other Provisions

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FDAAATitle IX Postmarket Safety of Drugs

,

contains new FDA authorities to:

Require sponsors to make safety related labeling changes Require sponsors to develop and comply with risk evaluation

and mitigation strategies (REMS)

Subtitle A took effect March 25, 2008

man ate to eve op an en ance a ty

to monitor the safety of drugs after these products

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Requirements for Post-Marketing

310.305 Prescription drugs without Approved Application

. -

314.98- Generic drugs Abbreviated NDA (ANDA)

. -

Section 760 of Food Drug and Cosmetic Act

Dietary Supplement and Nonprescription Drug Consumer

Protection Act

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Self-implementing law

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Highlights of Required Adverse

Serious adverse experience - Results in any of

Death

Life-threatening adverse experience

Inpatient hospitalization new or prolonged Persistent/significant disability/incapacity

Others medical judgment jeopardize the patient and

require intervention to prevent serious outcome Nonserious: Not serious

Unexpected: Not in the current labeling

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xpec e : n e curren a e ng

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Highlights of Required

All marketed drugs have reporting requirements tosubmit expedited reports (15 day)

serious, unexpected adverse events

or some pro uc s, expe e repor s o ser ous

adverse events

Drugs with approved applications also have

re uirements to submit Periodic re orts of otheradverse events, including other safety-related info

(actions taken due to adverse events)

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Every 3 months or every year

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Laws & Regulations Are Enforceable

Work with CDERs Office of Compliance

If the company introduces a drug into interstate

commerce in violation of provisions

If company fails to comply with REMS,

postmarket study/clinical trial, or safety labeling

chan es re uirements

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Laws & Regulations Are Enforceable

What can FDA do? Issue an untitled letter

Issue a Warning Letter

, ,

FDA can impose civil penalties for certainviolations of the Act

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Guidances Guidances further describe FDAs

External audience

Non-binding on the industry

http://www.fda.gov/Drugs/GuidanceComplianceR

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Postmarketing Safety Reporting

Adverse Drug Experiences

u ance: os mar e ng verse

Experience Reporting for Human Drug and

u :

to Report

2001 Draft Guidance: Postmarketing Safety

Reporting for Human Drug and Biological Products

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Including Vaccines.

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Postmarketing Safety Reporting

2008 Draft Guidance: Providing Regulatory--

Individual Case Safety Reports

Reporting for Nonprescription Human DrugProducts Marketed without an A rovedApplication

2011 Draft Guidance: Postmarketin AdverseEvent Reporting for Medical Products and DietarySupplements During Pandemic Influenza

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Review and Evaluation ofSpontaneous

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How does post-marketing adverse event &

, ,

FDA MedWatch Manufacturer

o un ary o un ary

regulatory

requirements

FDA

Database

5% of all reports 95% of all reports

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Database

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AERS is a computerized

information database designed

to support the FDA's post-marketing safety surveillance

program for all approved drugs

and therapeutic biologic

products.

The FDA uses AERS to monitor

for new adverse events andmedication errors that might

occur with these marketed

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products.

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What is in AERS ?

Individual Case Safety Reports (ICSRs)

Medication Errors

FOR:

rugs an t erapeut c o og cs x +

Homeopathic Products

Tissue products, therapeutic blood products

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What is in AERS ?

5.5 million reports in AERS

Data since 1969 Over 700,000 reports in 2010

Paper submissions 3500 (voluntary) and 3500A (mandatory) forms

Electronic submissions of mandatory ICSRs International ICH* E2B(R2) standards

Majority of submissions today are submitted electronically

Medical Dictionary for Regulatory Activities (MedDRA) coding events and indications for use

For more information:http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/default.htm

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n erna ona on erence on armon sa on o ec n ca equ remen s orRegistration of Pharmaceuticals for Human Use

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Safety Evaluators,

Signal Identification Trigger could be AERS or other originating source

Review/analyze event reports using AERS

Provide evaluation of safety issues (adverse events and medicationerrors)

o a ora e w o er sc p nes

Collaborate with OND and other CDER offices as

Provide recommendations regarding potentialregulatory actions

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mmt

Diapositiva 39

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Diapositiva 39

mmt6 suggest moving this bullet point follow under the Signal Identification bullet aboveTRUFFAM; 08/08/2011

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When a Serious AE is Rare in the Population

pontaneous eports are ore se u

are u ser ous a verse even

Introduction Intensive case evaluation

Pre-marketing

Safety Data

Post-marketing Period

Look back at pre-marketing

sa e y a a ase

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Example: Felbamate and Aplastic

anemia developing while on felbamate

out , pat ents expose to

felbamate

Reporting rate in felbamate-

exposed: 200/million

Incidence in general population:

2/million/year

41Source: Nightingale SL. JAMA 1994;272:995

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When a Serious AE is Common in the Population

Spontaneous Reports are Less Useful

manifestation of the underlying disease

Introduction Intensive case

evaluationPre-marketing

Safety Data

Post-marketing Period

oo ac a pre-mar e ng

safety database Still hard to establishand uantif risk

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Spontaneous Reports: The Challenge

Rates (estimates) of adverse drug events can be, ...

Numerators (exact number and extent of adverse events)

Reporting by public not required Denominators (drug exposure) impossible to know

Number of prescriptions filled is not an absolute measure of exposuredue to non-compliance, misuse, abuse, etc.

Event Rate is not the same as

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Drug Utilization Analysts

Analyze data from drug utilizationdatabases

ccess o ou pa en , npa en , me ca

claims data

# prescriptions, # patients, concomitant

use, ura on o use an more

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Epidemiologists

Risk identification

Provide context for otential si nals Drug use data (denominator)

Background rates of adverse events (medical literature)

Review studies/protocols submitted by sponsors forepidemiologic studies to quantify risks

Conduct population-based epidemiologic studies to quantify riskand identify risk factors

- Through collaborations with outside investigators

Develop new surveillance capabilities

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Sentinel initiative

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Passive vs. Active Surveillance

Passive Surveillance

Spontaneous reporting

events cannot be determinedActive Surveillance

Both cases and non-cases are observed

Cases are defined by objective criteria

Denominators and baseline rates of adverse events aredetermined

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opu a on ase

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Sentinel Initiative - Goals Develop a national electronic safety monitoring system

Leverage multiple sources of electronic data by partnering with data

holders Healthcare systems, insurance companies, etc. 100,000,000 patients by July 1, 2012

Enhance active post-market monitoring of medical product safety More effectively look at common outcomes (e.g. MI, fractures)

Increase population basis, sample size Improved access to subgroups, special populations

se va a e me o s

Near real-time monitoring Common data model

ntegrate act ve surve ance w t current post-mar et sa etymonitoring systems

Sentinel will augment, not replace,

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existing safety monitoring systems

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Sentinel Initiative Components

Mini-Sentinel Pilot

Federal Partners Working Group

OMOP Observational Medical Outcomes Partnership

p: omop. n .org

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Risk Management

Risk management is an iterativeprocess of - ,

Developing and implementingstrategies tominimize its risks while reservin its benefits

Evaluatingtool effectiveness and reassessing the

benefit-risk balance, and Making adjustments, as appropriate, to the risk

minimization strategies to further improve the

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benefit-risk balance

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What is a REMS* ?

Risk Evaluation and Mitigation Strategy

Medication Guide (patient labeling)

ommun ca on p an ea care prov ers

Elements to assure safe use (ETASU)

Implementation system

assessments of the REMS

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-

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What are ETASUs?

A. Health care providers who prescribe the drug have particular,

B. Pharmacies, practitioners, or health care settings thatdispense the drug are specially certified;

C. The drug is dispensed to patients only in certain health care

settings, such as hospitals;D. The drug is dispensed to patients with evidence or other

documentation of safe use conditions, such as laboratorytest results;

E. Each atient usin the dru is sub ect to certain monitorin ;or

F. Each patient using the drug is enrolled in a registry

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Risk Management Analysts

Leads OSE review of Proposed risk management programs, such

(REMS)

s managemen program assessmen

Often OSE multidisciplinary team reviews Premarketing and Postmarketing

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Health Communications Analysts &

Review risk communication components of

risk management programs (such as REMS)

Review behavioral or comprehension

studies/protocols submitted by sponsors

Often relates to risk management program assessment

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What Actions Can FDA TakeBased on Postmarketing

a e y a a

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Safety in the Lifecycle of FDA-regulated Products

A Post-

Marketin

PNew SafetySafety Surveillance

O Concerns

Clinical TrialsObservational Studies

A

Other

Strategies & Actions to

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Post-marketing surveillance:

anges o sa e y sec ons o a e ng

Contraindications, Boxed Warning,

Warnings/Precautions, Adverse Reactions

Post-marketing requirement (PMR) studies

Risk evaluation and mitigation strategies (REMS)

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Removal of product from market

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Communicating NewSafet Information to the Public

FDA might:

Professional Letter

Issue an FDA Dru Safet Communications MedWatch email Safety Alerts

www.fda.gov/medwatch

and Providers website http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationf

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orPatientsandProviders/default.htm

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uestions

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